2-32144957-G-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_014946.4(SPAST):c.1637G>T(p.Gly546Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_014946.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 4 Pathogenic:1
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly546 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPAST protein function. This variant has not been reported in the literature in individuals with SPAST-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 546 of the SPAST protein (p.Gly546Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. -
SPAST-related disorder Uncertain:1
The SPAST c.1637G>T variant is predicted to result in the amino acid substitution p.Gly546Val. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. However, a different amino acid change at this position (p.Gly546Arg) was previously reported as de novo in an individual with spastic paraplegia (Polymeris et al. 2016. PubMedID: 27260292). Although we suspect that c.1637G>T (p.Gly546Val) may be pathogenic, the clinical significance of this variant is currently classified as uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.